The extracellular matrix (ECM) is essential for the integrity of all tissues. Its importance can easily be realized when the connective tissue in the lung is destroyed which then leads to emphysema. However, progress in the treatment of this disease has been slow because the etiology of the major forms of emphysema remain unresolved. Also, the available animal models do not mimic the human disease in many important respects. The aim of this proposal is to study a transgenic mouse model which suggests a new etiological agent, collagenase, in emphysema. The experimental approach is to further characterize these transgenic mice which express collagenase in the lung and suffer from emphysema. First, the specificity of transgene expression in different tissues will be examined by RNAse protection analysis. In situ hybridization will identify the cell type expressing the transgene. Next, the temporal regulation of transgene expression will be defined at various developmental stages. The expression levels of genes which may be perturbed by collagenase overexpression will be analyzed so as to define the overall regulation of lung ECM synthesis. The transgene will be bred on various genetic backgrounds to identify loci which modify the emphysema phenotype. To assess the utility of these mice as human disease models, a detailed histological analysis of the lungs with the electron microscope will be performed and the mice observed for secondary symptoms that arise from prolonged emphysema. The eventual aim of these studies is to understand the pathogenesis of emphysema and provide a defined animal model to follow the pathophysiology of the disease. This model could be used to examine therapeutic methods in preventing the development of emphysema which is only second to heart disease in contributing to major disability in the USA.